Insulin-stimulated mitochondrial adenosine triphosphate synthesis is blunted in skeletal muscles of high-fat-fed rats.
Physiologic elevation of insulin levels induces a significant increase in muscle adenosine triphosphate (ATP) synthesis rate in normal individuals, indicative of an appropriate acceleration in mitochondrial activity. However, the stimulatory effect of insulin is diminished in insulin-resistant patients. In the absence of similar data from preclinical models, the present study investigated the inhibitory effects of increased dietary fat intake on insulin-stimulated ATP synthesis rates in rats. After being placed on a high-fat diet for 8 weeks (n = 10), diet-induced obese male Sprague-Dawley rats were tested against age-matched control rats (n = 9) on a normal chow diet. Muscle ATP synthase flux rates were measured under anesthesia by in vivo (31)P saturation transfer both before and during a euglycemic-hyperinsulinemic clamp. The glucose infusion rates observed during the clamp revealed impaired peripheral insulin sensitivity in the high-fat-fed rats when compared with the age-matched control rats. Under baseline conditions (ie, low insulin), the muscle ATP synthesis rates of high-fat-fed rats were approximately 30% lower (P < .05) than those in chow-fed rats. Moreover, chow-fed animals showed a significant increase (25%, P < .05 vs basal) in muscle ATP synthesis activity upon insulin stimulation, whereas high-fat-fed animals displayed no substantial change. These data demonstrated for the first time in a preclinical model that the insulin challenge not only facilitates an improvement in the dynamic range of ATP turnover measurement by (31)P saturation transfer between normal and insulin-resistant rats, but also mimics challenge that is relevant for pharmacologic studies on antidiabetic drugs aimed at improving mitochondrial function.
Yerby
Brittany
B
Global Imaging Group, Novartis Institutes for BioMedical Research, Inc, Cambridge, MA 02139, USA.
Deacon
Richard
R
Beaulieu
Valerie
V
Liang
Jinsheng
J
Gao
Jiaping
J
Laurent
Didier
D
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004041:Dietary Fats; D007328:Insulin; D000255:Adenosine Triphosphate